ABSTRACT Non-medical use of opioids, including heroin and prescription opioid analgesics, is a significant and growing public health concern in the United States. Distribution of naloxone to patients and caregivers is increasingly used for emergent treatment of opioid overdose. The most common approach involves kits containing hypodermic needles; however, individuals who fear interaction with the criminal justice system (e.g., screening for a preexisting arrest warrant or arrest for opioid analgesic possession) may refrain from carrying prescribed naloxone. In addition, there are concerns regarding misuse of the hypodermic needles within the kits. The research objective of this R21 program is to apply novel fabrication technologies to create a microneedle-based small-scale device for emergent treatment of opioid overdose, which can autonomously detect a depressed heart rate and/or decreased oxygen saturation levels (associated with opioid overdose) and actuate skin penetration of one (or two) biodegradable microneedle arrays for subcutaneous delivery of naloxone over time. The microneedle device can be inexpensively produced ($5/microneedle device for materials and processing) and can treat (and re-treat) an opioid overdose without external actuation in an emergency setting. In addition, the microneedle device can treat opioid overdose when caregivers are unavailable. Moreover, the microneedle device has no potential for sharps injury and/or syringe misuse (e.g., reuse with other agents). Aim I will involve physical, chemical, and in vitro biological characterization of the biodegradable microneedle array that will be used to deliver naloxone. Aim II will involve mechanical characterization of the Gantrez-naloxone microneedles to confirm that this component of the microneedle device is appropriate for subcutaneous delivery. Aim III will involve in vivo characterization of the pharmacokinetics of microneedle device- delivered naloxone, comparisons with the traditional routes of intramuscular and intravenous naloxone delivery, and a pilot study to demonstrate the functionality of the microneedle device with a pig model. The milestone achievement for the program is that the rate of naloxone delivery with the microneedle device must be equivalent to that for either intramuscular delivery or intravenous delivery; in addition, the maximum concentration for microneedle delivery must be comparable to those for intramuscular delivery or intravenous delivery. The development of proof of concept microneedle devices with appropriate structure and function for autonomous detection and treatment of opioid overdose will enable future clinical studies. Dr. Narayan, Dr. Papich, Dr. McLaughlin, and Dr. Finlay will work with a leader in pain medicine, Dr. Andrew Lobonc, to develop a close relationship for characterization of several types of novel naloxone detection and naloxone delivery therapies. Even if the program is not entirely successful, the data obtained from biological, chemical, mechanical, and functional characterization studies will nevertheless serve as the basis for a structure-performance database for using small-scale devices to autonomously detect and treat opioid overdose.